Nectin-like proteins mediate axon–Schwann cell interactions along the internode and are essential for myelination

Abstract

Axon–glial interactions are critical for the induction of myelination and the domain organization of myelinated fibers. Although molecular complexes that mediate these interactions in the nodal region are known, their counterparts along the internode are poorly defined. We report that neurons and Schwann cells express distinct sets of nectin-like (Necl) proteins: axons highly express Necl-1 and -2, whereas Schwann cells express Necl-4 and lower amounts of Necl-2. These proteins are strikingly localized to the internode, where Necl-1 and -2 on the axon are directly apposed by Necl-4 on the Schwann cell; all three proteins are also enriched at Schmidt-Lanterman incisures. Binding experiments demonstrate that the Necl proteins preferentially mediate heterophilic rather than homophilic interactions. In particular, Necl-1 on axons binds specifically to Necl-4 on Schwann cells. Knockdown of Necl-4 by short hairpin RNA inhibits Schwann cell differentiation and subsequent myelination in cocultures. These results demonstrate a key role for Necl-4 in initiating peripheral nervous system myelination and implicate the Necl proteins as mediators of axo–glial interactions along the internode.

Six cadm/synCAM genes are expressed in the nervous system of developing zebrafish

“…5K,L). This finding may reflect the expression of cadm3 and 4 in both neurons and glial cells, as has been demonstrated in the mouse (Kakunaga et al, 2005;GruberOlipitz et al, 2006;Maurel et al, 2007;Spiegel et al, 2007).…”

“…To date, in addition to various combinations of Cadm to Cadm interactions (Takai et al, 2003;Maurel et al, 2007), two types of heterophilic binding partners have been identified, the nectins and class I-restricted T-cell-associated molecules (CRTAM). Furthermore, the intracellular tails of the Cadms have been shown to interact with several scaffolding molecules in various in vitro systems.…”

“…In contrast to Cadm1, Cadm3 and Cadm4 expression seems to be mostly restricted to neurons and glial cells (astrocytes, oligodendrocytes, and Schwann cells; Maurel et al, 2007;Spiegel et al, 2007). Recently, it has been proposed that a heterophilic interaction between Cadm3 and Cadm4 mediates Schwann cell adhesion to peripheral axons.…”

“…Recently, it has been proposed that a heterophilic interaction between Cadm3 and Cadm4 mediates Schwann cell adhesion to peripheral axons. Perturbation with dominant-negative forms of either Cadm3 or Cadm4 or knockdown of their expression blocks the myelination process (Maurel et al, 2007;Spiegel et al, 2007). Expression patterns and function of Cadm2 have not been reported to date.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…Myelination in mice is reduced in the absence of b-secretase-1 (Bace 1), an endopeptidase that may act in peripheral nerves by cleaving neuregulin-1 and enhancing neuregulin-1 signaling (Hu et al, 2006;Willem et al, 2006). Studies using neuronSchwann cell co-cultures also indicate that nectin-like (Necl) proteins on the axonal surface are required for myelination (Maurel et al, 2007;Spiegel et al, 2007).…”